mRNA/miRNA Regulation of Host Resistance and Control in HIV-1 Discordant Couples Abstract: Although development of a protective or therapeutic HIV-1 vaccine has not yet been successful, numerous reports have documented the existence of individuals who have natural resistance to HIV-1 infection despite high exposure (exposed uninfected or EU). Furthermore, a great deal of study has been directed at better understanding individuals who become HIV-1 infected but whose host response effectively controls HIV-1 replication and maintain plasma HIV-1 RNA at low levels (viral controllers or VC). Many studies have focused on characterizing both innate and acquired characteristics of EU and VC. Despite this, the biological basis for natural host control of HIV-1 is still poorly understood. We hypothesize that, whether primarily inherited, acquired or with features of both, states of host resistance to and control of HIV-1 infection are characterized by specific patterns of host gene expression. Since, increasingly, small RNAs called microRNAs (miRNAs) have been identified as key regulators of large networks of genes controlling many cellular functions including antiviral defense, we also propose that patterns of miRNA expression may capture specific characteristics of the host state of resistance to or control of HIV-1. However, the specimens needed to study this are difficult to obtain, since they require prospective follow-up and RNA collection from individuals with well-characterized HIV-1 exposure. During the course of conducting HIV-1 prevention clinical trials and an observational study in Africa, we have collected just such a set of specimens from HIV-1 serodiscordant heterosexual couples (one partner HIV-1 infected and the other HIV-1 uninfected). This unique specimen repository and associated data provide a rare opportunity to use this unique epidemiological database and associated whole blood RNA specimens to assess determinants of host response to HIV-1. Specifically we seek to evaluate the role of mRNA and miRNAs in regulating host response to HIV-1. As an exploratory effort, we propose to use these unique existing specimens for pilot studies to identify host gene expression patterns regulating resistance to or control of HIV-1 infection. Identification of such host pathways could provide critical insights and help develop novel approaches to prevent HIV-1 transmission or to treat HIV-1 infection. PUBLIC HEALTH RELEVANCE: We propose to use a unique specimen subset of samples from HIV-1 serodiscordant heterosexual couples (with one partner HIV-1 infected and the other HIV-1 uninfected) to identify gene expression patterns that regulate resistance to or control of HIV-1 infection. Identification of such pathways could provide critical insights toward new approaches to prevention or treatment of HIV-1 infection.